Angiotensin (Ang) II, the primary transducer peptide of the renin-Ang system (RAS), acts at two major receptors: type-1 (AT1R) and type-2 (AT2R). The majority of Ang II actions occur via AT1Rs, including antinatriuresis. Renal cross-transplantation studies have demonstrated that renal AT1Rs are both necessary and sufficient for the induction and sustainability of hypertension during Ang II infusion and that increased Na+ reabsorption in the renal proximal tubule (RPT) is the major determinant of this response. In contrast, the role of AT2Rs in the control of Na+ excretion and hypertension is less clearly defined. Recent studies from our laboratory have provided evidence for a major role of RPT AT2Rs in the inhibition of Na+ reabsorption. These studies have provided evidence that, instead of Ang II, des-aspartyl1-Ang II (Ang III) is the preferred AT2R agonist inducing natriuresis. Furthermore, we now have evidence for a defect in AT2R-mediated natriuresis in spontaneously hypertensive rats (SHR) that pre-dates the hypertension and is due, at least in part, to accelerated intrarenal Ang III metabolism. Overall, our results suggest that AT2R-induced natriruesis is defective and contributes to the pathogenesis of hypertension in SHR. The overall goal of this project is to elucidate the mechanisms of defective AT2R-mediated natriuresis in SHR. The project will focus on three specific aims: (1) To test the hypothesis that defective AT2R-mediated natriuresis is important in the pathogenesis of HT in SHR; (2) To test the hypothesis that impaired natriuresis in SHR is due to reduction of Ang III; and (3) To test the hypothesis that chronic AT2R activation can restore normal natriuresis and prevent HT in SHR. The project will apply a combination of state-of-the-art in vivo and cell and molecular techniques, including intrarenal Ang II and III measurements, to clarify the role of the AT2R in sodium excretion in hypertension. These studies will help define the pathophysiology of human primary hypertension, a disorder affecting one-quarter after adult population in the Western world.